Opinion

The need to accurately assess the effectiveness of biologic therapies for rheumatoid arthritis in real-world settings has seen an explosion in nationwide biologics registers. In this Perspectives article, the authors discuss how to make the most of data from such registers.

The presence of antinuclear antibodies (ANAs) is an important criterion for the classification of autoimmune diseases such as systemic lupus erythematosus, but the specificity of ANA tests is controversial. This Perspectives article critically discusses the methods used in ANA testing for different diseases, as well as ways to improve the use of these assays in clinical and research settings.

Necrotizing vasculitis is a classic lesion of polyarteritis nodosa (PAN) and a number of other disorders. This Perspectives article discusses how the characterization and understanding of PAN and related disorders has developed and enabled more-specific treatments.

The pathways by which cells modulate metabolism to attain optimal effector responses present numerous potential therapeutic targets in the context of rheumatic diseases. This article explores the ways in which selective manipulation of metabolic pathways might influence immune cell populations and provide protection from inflammation and disease.

Current osteoarthritis therapies cannot sufficiently target cartilage and guarantee a biological response owing to limitations in the delivery methods. This Perspectives article discusses how electrostatic interactions can be utilized to increase drug penetration and retention in cartilage to provide sustained intra-tissue delivery.

In 2016, two international organizations published recommendations for the management of psoriatic arthritis. This article reviews the development of the recommendations, considers their similarities and differences, and provides guidance on how to interpret and apply the recommendations in practice.

Biobanks are important tools for researchers investigating paediatric rheumatic diseases. In this Opinion article, the authors outline how standardization can improve sample and data sharing, providing examples from international biorepository networks.

A subset of lupus autoantibodies can penetrate nuclei and damage DNA in cells, with consequences for the pathophysiology of systemic lupus erythematosus as well as cancer risk. Noble et al. propose the lupus butterfly theory to explain the effects of these DNA-damaging lupus autoantibodies on the interplay between autoimmunity, DNA damage and cancer.

Ehrenstein and Wing assert that rituximab re-treatment can trigger a vicious circle of ever-rising levels of BAFF (B-cell-activating factor, also known as TNF ligand superfamily member 13B), increasing autoantibody production and worsening disease in some patients with SLE. They argue for combining B-cell depletion and BAFF blockade in patients with SLE who have post-rituximab flares characterized by high levels of antibodies to double-stranded DNA.

Extracellular vesicles (EVs) are a heterogeneous group of membrane-enclosed particles involved in a multitude of biological processes, including the development and homeostasis of cartilage tissue. In this Perspectives article, the authors describe the current knowledge of the functions of EVs in joint physiology and explore the therapeutic potential of EVs as tools to deliver biologically-active therapeutic agents to joints.

The contributions of key cytokines in rheumatoid arthritis (RA) pathogenesis, including TNF, IL-1, JAK-dependent cytokines, GM-CSF and chemokines, can be considered not only individually, but also in the context of an overall 'RA tissue response'. In this Opinion article, the authors provide an overview of the roles of cytokines in the innate, adaptive and stromal immune responses, and discuss how systematic analysis of cytokine pathways could yield new insights into disease pathogenesis and facilitate stratification for therapy.

Lipopolysaccharide derived from gastrointestinal microbiota contributes to systemic inflammation and obesity. Huang and Kraus propose that lipopolysaccharide is a major risk factor for osteoarthritis (OA), and suggest that therapeutic strategies for the reduction of systemic levels of lipopolysaccharide should be considered for prevention and treatment of OA.

This article presents the concept that Behçet disease and several spondyloarthropathies might have a common immunopathogenetic basis. The authors propose that barrier dysfunction in environmentally exposed organs, and aberrant innate immune reactions at sites of mechanical stress, trigger secondary adaptive immune CD8⁺T-cell responses characterized by prominent neutrophilic inflammation. The differential immunopathology of these 'MHC-I-opathies' could reflect antigenic differences in target tissues.

Treatment optimization studies have paved the way for success of new therapies in paediatric oncology. The majority of children with cancer are treated within treatment optimization study protocols (TOSPs), but this is not the case for children with common rheumatic diseases such as juvenile idiopathic arthritis. In this Opinion article, Niehues suggests the recruitment of children with rheumatic diseases into TOSPs, making use of rheumatology research networks already established, would secure standardized treatments and outcome measures and could improve patient care considerably.

Observational studies are increasingly used to evaluate the safety and effectiveness of drugs for rheumatoid arthritis, but these studies are limited by inherent biases, including confounding by indication. This Perspectives article describes how these methodological limitations could be overcome by using the active-comparator design and the new-user design.

Genetic factors play an important part in the disease heterogeneity observed in patients with rheumatoid arthritis (RA). Genome-wide association studies (GWAS) have linked common single-nucleotide polymorphisms with the risk of developing RA, but have also highlighted the genetic heterogeneity between Asian and European patients with this disease. In this Perspectives article, the authors discuss recent advances from GWAS in Asian patients with RA, and suggest that better knowledge of the interface between genetic and environmental factors could help our understanding of the disease.

Kim et al. hypothesize that IL-21 is crucial to the pathogenesis of primary Sjögren syndrome (pSS), focusing on evidence of an interplay between the innate and adaptive immune responses mediated by the effects of IL-21 on immune cells. This new perspective might ultimately offer insight into novel approaches to the treatment of pSS.

In this Perspectives article, the authors argue that the cells of the inflammatory infiltrate and the cytokine milieu provide multiple routes to bone destruction in inflammatory arthritis. They first summarize the physiological pathway of osteoclastogenesis, then present emerging evidence of the contribution of various cytokines and cell types to alternative pathways of osteoclast differentiation and activation.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the central nervous system that is associated with several immunosuppressive therapies. In this Opinion article, Calabrese and colleagues propose a ranking of immunosuppressive agents based on their risk of PML to support a better-informed decision-making process.

A screening program for hyperuricaemia and gout would aim to identify those individuals with elevated serum urate and thus enable intervention to prevent the onset of gout. However, the data supporting a role for screening in this setting is far from complete. Stamp and Dalbeth outline the important issues around a screening programme for hyperuricaemia and gout, and highlight areas where further research is required before such a programme could be considered.